This proposal is submitted in response to RFA-GA-94-028. In the human, studies of "prostate carcinogenesis," the epidemiology of prostate cancer, the familial distribution of prostatic neoplastic processes, and the prevention of prostate cancer could progress much more rapidly if we could overcome two important problems. Firstly, as reviewed by us recently, the pathological context of prostatic carcinoma, i.e., the aging prostate, is very complex morphologically. - As stated in a report of 50 consultants to the NCI, "The prostate is unique in presenting the pathologist with a bewildering array of many different forms that are difficult to classify into diagnostic and prognostic categories. It is still unclear which of the many types and degrees of lesions are premalignant and will progress." The definitions of all of the currently available, widely accepted endpoints are histopathological given the current state of our knowledge; and our understanding of the histopathology is limited. Even the nomenclature is controversial and applied with highly variable precision among different pathologists. Secondly, there are only two widely accepted endpoints in the study of carcinogenesis as it occurs in the human prostate: prostatic carcinoma and high grade prostatic intraepithelial neoplasia (PIN). As detailed in the body of this proposal, the most recent and largest morphometric study shows that, in 30% of patients with prostate cancer, PIN is of relatively limited value for studies that depend upon needle biopsies because it is present as two or fewer than two foci in the entire prostate. In all studied patients, high grade PIN (the best endpoint biomarker) had an average volume of 1.32 ml/prostate; and only 0.3 ml of this PIN was located more than 2 mm distant from prostate cancer. A much more widespread intermediate endpoint biomarker is needed. We have recently described a lesion that we believe has the potential to be such a marker, the prostatic enzyme-altered focus (EAF). We reported that these EA. share some phenotypic properties with PIN; however, they appear to be more numerous than PIN lesions. Most, perhaps all, EA. are morphologically benign. In the proposed research, we shall explore the phenotypic characteristics of these lesions, carry out a morphometric study to determine their locations and frequencies in prostates of various subgroups of patients, and study their locations relative to prostatic cancers and other prostatic diseases.